Abstract
Cardiac glycosides (CGs) or cardiotonic steroids, which constitute a group of naturally occurring compounds with a steroid-like structure, can act on Na+/K+-ATPase as a receptor and activate intracellular signaling messengers leading to a variety of cellular responses. Epidemiological studies have revealed that CGs, used for the treatment of cardiac disorders, may also be beneficial as anti-cancer agents. CGs, acting in combination with other chemotherapeutic agents, may significantly alter their efficiency in relation to cancer cell elimination, causing both sensitization and an increase in cancer cell death, and in some cases resistance to chemotherapy. Here we show the ability of CGs to modulate apoptotic response to conventionally used anti-cancer drugs. In combination with etoposide, CGs digoxin may enhance cytotoxic potential, thereby allowing the chemotherapeutic dose to be decreased and minimizing toxicity and adverse reactions. Mechanisms behind this event are discussed.
Funding source: Russian Science Foundation
Award Identifier / Grant number: 14-25-00056
Funding source: Russian Foundation for Basic Research
Award Identifier / Grant number: 14-04-01660-a and 14-04-31078-mol-a
Funding statement: This work was supported by a grant from the Russian Science Foundation (14-25-00056) (Figures 1–4, 7). The work in the authors’ laboratories is also supported by grants from the Russian Foundation for Basic Research (14-04-01660-a and 14-04-31078-mol-a) and the President of the Russian Federation for young scientists (to A.V.K.) (14.120.14.2849-MK), as well as the Stockholm and Swedish Cancer Societies, the Swedish Childhood Cancer Foundation and the Swedish Research Council.
Acknowledgments:
This work was supported by a grant from the Russian Science Foundation (14-25-00056) (Figures 1–4, 7). The work in the authors’ laboratories is also supported by grants from the Russian Foundation for Basic Research (14-04-01660-a and 14-04-31078-mol-a) and the President of the Russian Federation for young scientists (to A.V.K.) (14.120.14.2849-MK), as well as the Stockholm and Swedish Cancer Societies, the Swedish Childhood Cancer Foundation and the Swedish Research Council.
References
Adorisio, R., De Luca, L., Rossi, J., and Gheorghiade, M. (2006). Pharmacological treatment of chronic heart failure. Heart Failure Rev. 11, 109–123.10.1007/s10741-006-9482-zSearch in Google Scholar PubMed
Aizman, O., Uhlén, P., Lal, M., Brismar, H., and Aperia, A. (2001). Ouabain, a steroid hormone that signals with slow calcium oscillations. Proc. Natl. Acad. Sci. USA 98, 13420–13424.10.1073/pnas.221315298Search in Google Scholar PubMed PubMed Central
Bagrov, A., Shapiro, J., and Fedorova, O. (2009). Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol. Rev. 61, 9–38.10.1124/pr.108.000711Search in Google Scholar PubMed PubMed Central
Beheshti Zavareh, R.B., Lau, K.S., Hurren, R., Datti, A., Ashline, D.J., Gronda, M., Cheung, P., Simpson, C.D., Liu, W., Wasylishen, A.R., et al. (2008). Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function. Cancer Res. 68, 6688–6697.10.1158/0008-5472.CAN-07-6833Search in Google Scholar PubMed
Bielawski, K., Winnicka, K., and Bielawska, A. (2006). Inhibition of DNA topoisomerases I and II, and Growth inhibition of breast cancer MCF-7 cells by ouabain, digoxin and proscillaridin A. Biol. Pharm. Bull. 29, 1493–1497.10.1248/bpb.29.1493Search in Google Scholar PubMed
Brouillard, F., Tondelier, D., Edelman, A., and Baudouin-Legros, M. (2001). Drug resistance induced by ouabain via the stimulation of MDR1 gene expression in human carcinomatous pulmonary cells. Cancer Res. 61, 1693–1698.Search in Google Scholar
De Lange, E. (2004). Potential role of ABC transporters as a detoxification system at the blood-CSF barrier. Adv. Drug Delivery Rev. 14, 1793–1809.10.1016/j.addr.2004.07.009Search in Google Scholar PubMed
Fontana, J.M., Burlaka, I., Khodus, G., Brismar, H., and Aperia, A. (2013). Calcium oscillations triggered by cardiotonic steroids. FEBS J. 280, 5450–5455.10.1111/febs.12448Search in Google Scholar PubMed
Frese, S., Frese-Schaper, M., Andres, A., Miescher, D., Zumkehr, B., and Schmid, R. (2006). Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5. Cancer Res. 66, 5867–5874.10.1158/0008-5472.CAN-05-3544Search in Google Scholar PubMed
Gao, Y., Li, H.X., Xu, L.T., Wang, P., Xu, L.Y., Cohen, L., Yang, P.Y., Gu, K., and Meng, Z.Q. (2012). Bufalin enhances the anti-proliferative effect of sorafenib on human hepatocellular carcinoma cells through downregulation of ERK. Mol. Biol. Rep. 39, 1683–1689.10.1007/s11033-011-0908-xSearch in Google Scholar PubMed
Haux, J. (1999). Digitoxin is a potential anticancer agent for several types of cancer. Med. Hypoth. 53, 543–548.10.1054/mehy.1999.0985Search in Google Scholar PubMed
Haux, J., Klepp, O., Spigset, O., and Tretli, S. (2001). Digitoxin medication and cancer; case control and internal dose-response studies. BMC Cancer 1, 11–17.10.1186/1471-2407-1-11Search in Google Scholar PubMed PubMed Central
Huang, D., Guh, J., Huang, Y., Chueh, S., Wang, H., and Teng, C. (2002). Cardiac glycosides induce resistance to tubulin-dependent anticancer drugs in androgen-independent human prostate cancer. J. Biomed. Sci. 9, 443–452.10.1007/BF02256539Search in Google Scholar PubMed
Kishimoto, S., Kawazoe, Y., Ikeno, M., Saitoh, M., Nakano, Y., Nishi, Y., Fukushima, S., and Takeuchi, Y. (2006). Role of Na+, K+-ATPase α1 subunit in the intracellular accumulation of cisplatin. Cancer Chemother. Pharmacol. 57, 84–90.10.1007/s00280-005-0003-xSearch in Google Scholar PubMed
Kometiani, P., Liu, L., and Askari, A. (2005). Digitalis-induced signaling by Na/K-ATPase in human breast cancer cells. Mol. Pharmacol. 67, 929–936.10.1124/mol.104.007302Search in Google Scholar PubMed
Kramer, R., Weber, T., Arceci, R., Ramchurren, N., Kastrinakis, W., Steele, G., and Summerhayes, I. (1995). Inhibition of N-linked glycosylation of P-glycoprotein by tunicamycin results in a reduced multidrug resistance phenotype. Br. J. Cancer 71, 670–675.10.1038/bjc.1995.133Search in Google Scholar PubMed PubMed Central
Lawrence, T. and Davis, M. (1990). The influence of Na+, K+-pump blockade on doxorubicin-mediated cytotoxicity and DNA strand breakage in human tumor cells. Cancer Chemother. Pharmacol. 26, 163–167.10.1007/BF02897193Search in Google Scholar PubMed
Lawrence, T., Canman, C., Maybaum, J., and Davis, M. (1989). Dependence of etoposide-induced cytotoxicity and topoisomerase II-mediated DNA strand breakage on the intracellular ionic environment. Cancer Res. 49, 4775–4779.Search in Google Scholar
López-Lázaro, M., Pastor, N., Azrak, S., Ayuso, M., Austin, C., and Cortés, F. (2005). Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients. J. Natural. Prod. 68, 1642–1645.10.1021/np050226lSearch in Google Scholar PubMed
López-Lázaro, M., Pastor, N., Azrak, S., Ayuso, M., Cortés, F., and Austin, C. (2006). Digitoxin, at concentrations commonly found in the plasma of cardiac patients, antagonizes etoposide and idarubicin activity in K562 leukemia cells. Leukemia Res. 30, 895–898.10.1016/j.leukres.2005.11.005Search in Google Scholar PubMed
McConkey, D., Lin, Y., Nutt, L., Ozel, H., and Newman, R. (2000). Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res. 60, 3807–3812.Search in Google Scholar
Menger, L., Vacchelli, E., Kepp, O., Eggermont, A., Tartour, E., Zitvogel, L., Kroemer, G., and Galuzzi, L. (2013). Cardiac glycosides and cancer therapy trial watch. Oncoimmunology 2, 1–7.10.4161/onci.23082Search in Google Scholar PubMed PubMed Central
Mijatovic, T. and Kiss, R. (2013). Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways. Planta Medica 79, 189–198.10.1055/s-0032-1328243Search in Google Scholar PubMed
Mijatovic, T., Jungwirth, U., Heffeter, P., Reza Hoda, M., Dornetshuber, R., Kiss, R., and Berger, W. (2009). The Na+/K+-ATPase is the Achilles heel of multi-drug-resistant cancer cells. Cancer Lett. 282, 30–34.10.1016/j.canlet.2009.02.048Search in Google Scholar
Orrenius, S., Kaminskyy, V.O., and Zhivotovsky, B. (2012). Autophagy in toxicology: cause or consequence? Annu. Rev. Pharmacol. Toxicol. 53, 275–297.10.1146/annurev-pharmtox-011112-140210Search in Google Scholar
Panayiotidis, M.I., Franco, R., Bortner, C.D., and Cidlowski, J.A. (2010). Ouabain-induced perturbations in intracellular ionic homeostasis regulate death receptor-mediated apoptosis. Apoptosis 15, 834–849.10.1007/s10495-010-0494-8Search in Google Scholar
Prassas, I., Paliouras, M., Datti, A., and Diamandis, E.P. (2008). High-throughput screening identifies cardiac glycosides as potent inhibitors of human tissue kallikrein expression: implications for cancer therapies. Clin. Cancer Res. 14, 5778–5784.10.1158/1078-0432.CCR-08-0706Search in Google Scholar
Riganti, C., Campia, I., Polimeni, M., Pescarmona, G., Ghigo, D., and Bosia, A. (2009). Digoxin and ouabain induce P-glycoprotein by activating calmodulin kinase II and hypoxia-inducible factor-1α in human colon cancer cells. Toxicol. Appl. Pharmacol. 240, 385–392.10.1016/j.taap.2009.07.026Search in Google Scholar
Schneider, V., Krieger, M.L., Bendas, G., Jaehde, U., and Kalayda, K.V. (2013). Contribution of intracellular ATP to cisplatin resistance of tumor cells. J. Biol. Inorg. Chem. 18, 165–174.10.1007/s00775-012-0960-6Search in Google Scholar
Schoner, W. and Scheiner-Bobis, G. (2007). Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth. Am. J. Physiol. Cell Physiol. 293, 509–536.10.1152/ajpcell.00098.2007Search in Google Scholar
Smith, J.A., Madden, T., Vijjeswarapu, M., and Newman, R.A. (2001). Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by anvirzel and its cardiac glycoside component, oleandrin. Biochem. Pharmacol. 62, 469–472.10.1016/S0006-2952(01)00690-6Search in Google Scholar
Soldani, C. and Scovassi, A.I. (2002). Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis 7, 321–328.10.1006/excr.2001.5293Search in Google Scholar PubMed
Strick, R., Strissel, P.L., Gavrilov, K., and Levi-Setti, R. (2001). Cation-chromatin binding as shown by ion microscopy is essential for the structural integrity of chromosomes. J. Cell Biol. 155, 899–910.10.1083/jcb.200105026Search in Google Scholar PubMed PubMed Central
Tailler, M., Senovilla, L., Lainey, E., Thépot, S., Métivier, D., Sébert, M., Baud, V., Billot, K., Fenaux, P., Galluzzi, L., Boehrer, S., Kroemer, G., and Kepp, O. (2012). Antineoplastic activity of Ouabain and Pyrithione zinc in acute myeloid leukemia. Oncogene 31, 3536–3546.10.1038/onc.2011.521Search in Google Scholar
Takara, K., Takagi, K., Tsujimoto, M., Ohnishi, N., and Yokoyama, T. (2003). Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously down-regulates steroid xenobiotic receptor mRNA. Biochem. Biophys. Res. Commun. 306, 116–120.10.1016/S0006-291X(03)00922-7Search in Google Scholar
Trenti, A., Grumati, P., Cusinato, F., Orso, G., Bonaldo, P., and Trevisi, L. (2014). Cardiac glycoside ouabain induces autophagic cell death in non-small cell lung cancer cells via a JNK-dependent decrease of Bcl-2. Biochem. Pharmacol. 89, 197–209.10.1016/j.bcp.2014.02.021Search in Google Scholar
Verheye-Dua, F. and Bohm, L. (1998). Na+, K+-ATPase inhibitor, Ouabain, accentuates irradiation damage in human tumour cell lines. Radiat. Oncol. Investig. 6, 109–119.10.1002/(SICI)1520-6823(1998)6:3<109::AID-ROI1>3.0.CO;2-1Search in Google Scholar
Winnicka, K., Bielawski, K., and Bielawska, A. (2006). Cardiac glycosides in cancer research and cancer therapy. Acta Pol. Pharm. 63, 109–115.Search in Google Scholar
Xie, Z. and Askari, A. (2002). Na+ /K+-ATPase as a signal transducer. Eur. J. Biochemi. 269, 2434–2439.10.1046/j.1432-1033.2002.02910.xSearch in Google Scholar
Xie, C.M., Chan, W.Y., Yu, S., Zhao, J., and Cheng, C.H. (2011). Bufalin induces autophagy-mediated cell death in human colon cancer cells through reactive oxygen species generation and JNK activation. Free Radic. Biol. Med. 51, 1365–1375.10.1016/j.freeradbiomed.2011.06.016Search in Google Scholar
Xu, Z.W., Wang, F.M., Gao, M.J., Chen, X.Y., Shan, N.N., Cheng, S.X., Mai, X., Zala, G.H., Hu, W.L., and Xu, R.C. (2011). Cardiotonic steroids attenuate ERK phosphorylation and generate cell cycle arrest to block human hepatoma cell growth. J. Steroid Biochem. Mol. Biol. 125, 181–191.10.1016/j.jsbmb.2010.12.016Search in Google Scholar
Zhang, H., Qian, D.Z., Tan, Y.S., Lee, K., Gao, P., Ren, Y.R., Rey, S., Hammers, H., Chang, D., Pili, R., et al. (2008). Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc. Natl. Acad. Sci. USA 105, 19579–19586.10.1073/pnas.0809763105Search in Google Scholar
©2016 by De Gruyter
Articles in the same Issue
- Frontmatter
- Guest Editorial
- Mitochondria, redox signaling and cell death in cancer
- HIGHLIGHT: EMBO WORKSHOP “MITOCHONDRIA, APOPTOSIS AND CANCER 2015”
- The anti-oxidant and pro-oxidant dichotomy of Bcl-2
- Mitosis and mitochondrial priming for apoptosis
- The role of Her2 and other oncogenes of the PI3K/AKT pathway in mitochondria
- Mechanisms of mitophagy: putting the powerhouse into the doghouse
- Controlling quality and amount of mitochondria by mitophagy: insights into the role of ubiquitination and deubiquitination
- Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum
- Regulation of necroptosis signaling and cell death by reactive oxygen species
- Contrasting effects of cardiac glycosides on cisplatin- and etoposide-induced cell death
- iBH3: simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry
- Review
- The impact of recent advances in genetics in understanding disease mechanisms underlying the long QT syndromes
Articles in the same Issue
- Frontmatter
- Guest Editorial
- Mitochondria, redox signaling and cell death in cancer
- HIGHLIGHT: EMBO WORKSHOP “MITOCHONDRIA, APOPTOSIS AND CANCER 2015”
- The anti-oxidant and pro-oxidant dichotomy of Bcl-2
- Mitosis and mitochondrial priming for apoptosis
- The role of Her2 and other oncogenes of the PI3K/AKT pathway in mitochondria
- Mechanisms of mitophagy: putting the powerhouse into the doghouse
- Controlling quality and amount of mitochondria by mitophagy: insights into the role of ubiquitination and deubiquitination
- Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum
- Regulation of necroptosis signaling and cell death by reactive oxygen species
- Contrasting effects of cardiac glycosides on cisplatin- and etoposide-induced cell death
- iBH3: simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry
- Review
- The impact of recent advances in genetics in understanding disease mechanisms underlying the long QT syndromes